Skip to main content
SpringerLink
Log in

Down regulation of kidney neutral endopeptidase mRNA, protein and activity during acute renal failure: Possible mechanism for ischemia-induced acute renal failure in rats?

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Neutral endopeptidase (NEP, 24.11) is an ectoenzyme involved in the degradation of peptide hormones such as endothelin (ET), atrial natriuretic factor and enkephalins. The current study was designed to assess the involvement of NEP in ischemia-induced acute renal failure (ARF). In unilaterally nephrectomized Sprague-Dawley rats, the left renal artery was occluded for 30 min under pentobarbital anesthesia (40 mg/kg, i.p.) at 37°C. In addition to plasma creatinine levels, NEP activity was determined in renal cortical membranes at 0, 2, 5, and 24 h following reperfusion. Plasma creatinine levels significantly increased at 2, 5 and 24 h. There was a significant decrease in NEP activity as early as 2 h following reperfusion that was maintained up to 24 h (57.9 ± 4%) with a concomitant loss of enzyme protein shown by Western analysis. Northern analysis of kidney cortical RNA, probed with an NEP cDNA, showed a 45% decrease in NEP mRNA level by the end of the ischemic period and decreased further during reperfusion. Thus, decrease in NEP mRNA levels preceded the changes in protein level, enzyme activity and plasma creatinine levels. These data, along with the reported increase in the tissue level of ET in kidney cortex, and the beneficial effect of ET antibody as well as ET receptor antagonist in ARF, suggest that down regulation of NEP, one of the mechanisms leading to increased tissue level of ET, may be a contributing factor to ARF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hostetter TH, Wilkes B, Brenner BM: WB Saunders, Philadelphia, 1983, pp 99–115

  2. Conger JD, Robinette JB, Hammond WS: Differences in vascular reactivity in models of ischemic acute renal failure. Kidney Int 39: 1087–1097, 1991

    Google Scholar 

  3. Hollenberg NK, Wilkes BM, Schulman G: In: BM Brenner, JM Lazarus (eds). Acute Renal Failure. 2nd ed., Churchill Livingstone, London, 1988, pp 119–141

    Google Scholar 

  4. Conger JD, Robinette JB, Schrier RW: Smooth muscle calcium and endothelium derived relaxing factor in the abnormal vascular responses of acute renal failure. J Clin Invest 82: 532–537, 1988

    Google Scholar 

  5. Yanagisawa H, Kurihara H, Kimura S, Tombe Y, Kobayashi M, Matsui Y, Yazakis Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415, 1988

    Google Scholar 

  6. Goetz KL, Wang BC, Madwed JB, Zhu JL, Leadley RJ: Cardiovascular, renal and endocrine responses to intravenous endothelin in conscious dogs. Am J Physiol.255: R1064–R1068, 1988

    Google Scholar 

  7. King AJ, Brenner BM, Anderson S: Endothelin: A potent renal and systemic vasoconstrictor peptide. Am J Physiol 256: F1051–F1058, 1989

    Google Scholar 

  8. Miller WL, Redfield MM, Burnette JC: Integrated cardiac, renal and endocrine actions of endothelin. J Clin Invest 83: 317–320, 1989

    Google Scholar 

  9. Baley PA, Resink TJ, Eppenberger U, Hahn AWA: Endothelin messenger RNA and receptors are differentially expressed in cultured human breast epithelial and stromal cells. J Clin Invest 85: 1320–1323, 1990

    Google Scholar 

  10. Nunez DJ, Brown MJ, Davenport AP, Neylon CB, Schofield JP, Wyse RK: Endothelin-1 mRNA is widely expressed in porcine and human tissues. J Clin Invest 85: 1537–1541, 1990

    Google Scholar 

  11. Simonson MS, Dunn MJ: Cellular signaling by peptide of the endothelin gene family. FASEB J 4: 2989–3000, 1990

    Google Scholar 

  12. Bakris GL, Fairbanks R, Traish AM: Arginine vasopressin stimulates human mesangial cell production of ET. J Clin Invest 87: 1158–1164, 1991

    Google Scholar 

  13. Kosaka T, Suzuki N, Matsumoto H, Itoh Y, Yasuhara T, Onda H, Fujino M: Synthesis of the vasoconstrictor peptide endothelin in kidney cells. FEBS Lett 249: 42–46, 1989

    Google Scholar 

  14. Ohta K, Hirata Y, lmai T, Kanno K, Emori T, Shichiri H, Marumo F: Cytokine-induced release of ET-1 from porcine renal epithelial cell line. Biochem Biophys Res Commun 169: 578–584, 1990

    Google Scholar 

  15. Zoja C, Orisio S, Perico N, Benigni A, Morigi M, Benatti L, Rambaldi A, Remuzzi G: Constitutive expression of ET gene in cultured human mesangial cells and its modulation by transforming growth factor β, thrombin and a thromboxane A2 analog. Lab Invest 64: 16–20, 1991

    Google Scholar 

  16. Vijayaraghavan J, Scicli AG, Carretero OA, Slaughter C, Moomaw C, Hersh LB: The hydrolysis of endothelins by neutral endopeptidase 24.11 (enkephalinase). J Biol Chem 265: 14150–14156, 1990

    Google Scholar 

  17. Abassi ZA, Tate JE, Golomb E, Keiser HR: Role of neutral endopeptidase in the metabolism of endothelin. Hypertension 20: 89–95, 1992

    Google Scholar 

  18. Hoyer D, Waeber C, Palacious JM: [125I]-ET-1 endothelin-1 binding sites: Autoradiographic studies in the brain and periphery of various species including humans. J Cardiovasc Pharmacol 13(suppl 5): S162–S165, 1989

    Google Scholar 

  19. Martin ER, Brenner BM, Ballerman BJ: Heterogeneity of cell surface endothelin receptors. J Biol Chem 265: 14044–14049, 1990

    Google Scholar 

  20. Nambi P, Pullen M, Feuerstein G: Identification of endothelin receptors in various regions of rat brain. Neuropeptides 16: 195–199, 1990

    Google Scholar 

  21. Nambi P, Pullen M, Wu H-L, Aiyar N, Ohlstein EH, Edwards RM: Identification of endothelin receptor subtypes in human renal cortex and medulla using subtype-selective ligands. Endocrinology 131: 1081–1086, 1992

    Google Scholar 

  22. Wilkes BM, Mento PF, Hollander AM, Maita ME, Sung S, Girardi EP: Endothelin receptors in human placenta: Relationship to vascular resistance and thromboxane release. Am J Physiol 258: E864–E870, 1990

    Google Scholar 

  23. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S: Cloning and expression of a cDNA encoding an endothelin receptor. Nature (London) 348: 730–732, 1990

    Google Scholar 

  24. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki M, Kimura S, Goto K, Masaki T: Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature (London) 348: 732–735, 1990

    Google Scholar 

  25. Elshourbagy N, Korman D, Nuthulaganti P, Wu H-L, Sylvester D, Kumar C, Bergsma D, Nambi P: Molecular characterization and regulation of the human endothelin receptors. J Biol Chem 268: 3873–3879, 1993

    Google Scholar 

  26. Pericho N, Dadan J, Remuzzi G: Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat. J Am Soc Nephrol 1: 76–83, 1990

    Google Scholar 

  27. Kon V, Sigiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL: Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int 37: 1487–1491, 1990

    Google Scholar 

  28. Cornet S, Braillon A, Guilmard C, Chabrier PE, Pirotzky E, Braquet P. Involvement of endothelin in renal processes. Hypertension 15: 724–728, 1990

    Google Scholar 

  29. Koyama H, Tabata T, Nishizawa Y, Inoue T, Morii Y, Yamaji T: Plasma endothelin levels in patients with uremia. Lancet 1: 991–992, 1989

    Google Scholar 

  30. Kon V, Yoshioka T, Fogo A, Ichikawa I: Glomerular actions of endothelin in vivo. J Clin Invest 83: 1762–1767, 1989

    Google Scholar 

  31. Shibouta Y, Suzuki N, Shino A, Matsumoto H, Terashita Z-I, Kondo K, Nishikawa K: Pathophysiological role of endothelin in acute renal failure. Life Sci 46: 1611–1618, 1990

    Google Scholar 

  32. Mino N, Kobayashi M, Nakajima A, Amano H, Shimamoto K, Ishikawa K, Watanabe K, Nishikebe M, Yano M, Ikemoto F: Protective effect of a selective endothelin receptor antagonist, BQ123, in ischemic acute renal failure in rats. Eur J Pharmacol 221: 77–83, 1992

    Google Scholar 

  33. Gellai M, Jugus M, Fletcher T, DeWolf R, Nambi P: Reversal of post-ischemic acute renal failure with a selective ETA receptor antagonist in the rat. J Clin Invest 93: 900–906, 1994

    Google Scholar 

  34. Gellai M, Jugus M, Fletcher T, Nambi P, Ohlstein EH, Elliott JD, Brooks DP: Nonpeptide endothelin receptor antagonists. V. Prevention and reversal of acute renal failure in the rat by SB 209670. J Pharmacol Exp Ther 275: 200–206, 1995

    Google Scholar 

  35. Nambi P, Pullen M, Jugus M, Gellai M: Rat kidney endothelin receptors in ischemia-induced acute renal failure. J Pharmacol Exp Ther 264: 345–348, 1993

    Google Scholar 

  36. Hersh L, Morihara K: Comparison of the substrate specificity of the mammalian neutral endopeptidase 24.11 (enkephalinase) to the bacterial neutral endopeptidase thermolysin. J Biol Chem 261: 6433–6437, 1986

    Google Scholar 

  37. Dickinson KEJ, Tymiak AA, Cohen RB, Liu ECK, Webb ML, Hedberg A: Vascular A10 cell membranes contain an endothelin metabolizing neutral endopeptidase. Biochem Biophys Res Commun 176: 423–430, 19??

  38. Vida TA, Hersh LB: Glycosylation variants of endopeptidase 24.11 ('Enkephalinase'). Neuropeptides 21: 245–255, 1992

    Google Scholar 

  39. Chomczynski P, Sachi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159, 1987

    Google Scholar 

  40. Lehrarch H, Diamond D, Wozney JM, Boedtker H: RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochem 16: 4793–4751, 1977

    Google Scholar 

  41. Bateman RC Jr, Jackson D, Slaughter CA, Unnithan S, Chai Y-G, Moomaw C, Hersh LB: Identification of the active-site arginine in rat neutral endopeptidase 24.11 (enkephalinase) as arginine 102 and analysis of a glutamine 102 mutant. J Biol Chem 264: 6151–6157, 1989

    Google Scholar 

  42. Lopez-Farre A, Gomez-Garre D, Bernabeu F, Lopez-Novoa JM: A role for ET-1 in the maintenance of post-ischemic renal failure in the rat. J Physiol 444: 513–522, 1991

    Google Scholar 

  43. Devault A, Lazure C, Nault C, Lemonal H, Seidah NG, Chretien M, Kahn P, Powell J, Mallet J, Beaumont A, Roques BP, Crine P, Boileau G: Amino acid sequence of rabbit kidney neutral endopeptidase 24.11 (enkephalinase) deduced from a complimentary DNA. Embo J 6: 1317–1322, 1987

    Google Scholar 

  44. Bazan N-G: Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain. Biochim Biophys Acta 218: 1–10, 1970

    Google Scholar 

  45. Abe K, Kogure K, Yammamoto H, Imazawa M, Miyamoto K: Mechanism of arachidonic acid liberation during ischemia in gerbil cerebral cortex. J Neurochem 48: 503–509, 1987

    Google Scholar 

  46. Yoshimura T, Mayumi M, Yorifuji T, Kim KM, Heike T, Miyanomae T, Shinomiya K, Mikawa H: Glomeruli from ischemic rat kidneys produce increased amounts of platelet activating factor. Am J Hematol 26: 47–54, 1987

    Google Scholar 

  47. Onodera H, Araki T, Kogure K: Protein kinase C activity in the rat hippocampus after forebrain ischemia: Autoradiographic analysis by [3H] phorbol 12,13–dibutyrate. Brain Res 481: 1–7, 1989

    Google Scholar 

  48. Werb Z, Clark EJ: Phorbol diesters regulate expression of the membrane neutral metalloendopeptidase (EC.3.4.24.11) in rabbit synovial fibroblast and mammary epithelial cells. J Biol Chem 264: 9111–9113, 1989

    Google Scholar 

  49. Lopez-Farre A, Torralbo M, Lopez-Novoa JM: Down regulation and inactivation of neutral endopeptidase 24.11 (enkephalinase) in human neutrophils. Biochem Biophys Res Commun 152: 129–135, 1988

    Google Scholar 

  50. Erdos EG, Waynes B, Hashney CB, Painter RG, Skidgel RA, Fa YG: Establishment of a common acute lymphoblastic leukemia cell line (LC4–1) and effects of phorbol myristate acetate (PMA) on the surface antigen expression of the cell line. J Biol Chem 264: 14519–14524, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA

    Ponnal Nambi, Uma Prabhakar & Mikios Gellai

  2. Department of Cellular Biochemistry and Immunology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA

    Louis Hersh

Authors
  1. Ponnal Nambi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hsiao-Ling Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uma Prabhakar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louis Hersh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mikios Gellai
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nambi, P., Wu, HL., Prabhakar, U. et al. Down regulation of kidney neutral endopeptidase mRNA, protein and activity during acute renal failure: Possible mechanism for ischemia-induced acute renal failure in rats?. Mol Cell Biochem 197, 53–59 (1999). https://doi.org/10.1023/A:1006913103720

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006913103720

Search

Navigation